Genetics and biological significance of the HLA system
The major histocompatibility complex system was originally discovered through the study of transplant rejection reactions. This is why the surface proteins of this family in humans were named Human Leucocyte Antigens (HLA).
The genetic apparatus of this system is located on the short arm of chromosome 6 (region 6p21.31). This is an extensive region comprising over two hundred genes that encode special glycoproteins. A key feature of this complex is the extremely high degree of variability (polymorphism) of class I and II genes. A vast multitude of allele variations forms a unique, inimitable set of surface cellular markers for each individual. The only people in the world with an absolutely identical histocompatibility profile are identical twins.
Classification and localization of molecules
Traditionally, the genes and proteins of this family are divided into three classes depending on their functions, structure, and location.
- Class I MHC (represented by HLA-A, HLA-B, HLA-C types). These molecules are present on the membranes of absolutely all nucleated cells in our body. They serve as a peculiar molecular "passport". There are few exceptions to this rule: MHC I molecules are absent on erythrocytes (which lack a nucleus), neurons, and villous trophoblast cells.
- Class II MHC (HLA-DR, HLA-DP, HLA-DQ types). Normally, they are located exclusively on professional antigen-presenting cells (APCs), which include macrophages, dendritic cells, and B lymphocytes. Under certain conditions, such as activation by $\gamma$-interferon, their appearance can be induced on T lymphocytes, endothelium, and epithelium.
- Class III MHC. Unlike the first two, these genes encode molecules that do not participate in antigen presentation. Their products are soluble immune mediators: complement system components and important cytokines (such as tumor necrosis factor $\alpha$ and lymphotoxin).
Molecular structure
Histocompatibility molecules involved in antigen presentation have a similar structural principle but differ in important details. The basis of the receptor is the antigen-binding cleft (Bjorkman groove).
Structure of a class I MHC molecule The receptor is formed by two non-covalently linked polypeptide chains. The heavy $\alpha$-chain contains three domains: $\alpha_1$, $\alpha_2$, and $\alpha_3$. The $\beta_2$-microglobulin molecule acts as the light chain. The Bjorkman groove is located between the $\alpha_1$ and $\alpha_2$ domains. This hypervariable region binds small short peptides ranging from 8 to 10 amino acid residues in length.
Structure of a class II MHC molecule This molecule has a more complex structure and consists of two full-length polypeptide chains: $\alpha$ and $\beta$. Each chain contributes two domains (forming an $\alpha_1$, $\alpha_2$ and $\beta_1$, $\beta_2$ organization). The Bjorkman groove here is formed by the joint efforts of both chains ($\alpha_1$ and $\beta_1$ domains participate). Due to this design, the capacity of the groove is significantly greater—it holds peptides ranging from 12 to 25 amino acid residues in length.
Mechanisms of antigen processing and presentation
The main role of MHC is to demonstrate to the immune system what is happening inside or around the cell. The process of preparing a foreign protein is called processing, and displaying it on the surface is called presentation.
MHC I pathway (endogenous antigens) Through this pathway, the cell displays what is synthesized inside it (e.g., viral proteins during infection or mutant tumor proteins).
- Intracellular proteins are cleaved in the proteasome into short peptides.
- Peptides are transported into the endoplasmic reticulum (ER).
- The "peptide + MHC I molecule" complex is formed in the ER.
- The ready complex is sent to the membrane, where it is recognized by cytotoxic T lymphocytes (CD8+ phenotype). The CD8 coreceptor binds to the invariant $\alpha_3$ domain, stabilizing the contact.
MHC II pathway (exogenous antigens) Used by antigen-presenting cells (APCs) to present pathogens captured from the outside.
- The APC engulfs the pathogen via phagocytosis or endocytosis.
- The pathogen enters a vesicle, where it is degraded (processed) into fragments. Simultaneously, MHC II molecules are synthesized in the ER.
- The antigen fragment binds to the MHC II molecule, after which the complex is transported to the membrane.
- The addressee of such presentation is a naive T helper ($T_H0$) with the CD4+ phenotype.
Upon recognition of the complex, the naive T helper is activated and differentiates. If it becomes a type 1 helper ($T_H1$), it secretes cytokines to activate cellular immunity. If it turns into a $T_H2$, it secretes substances that stimulate the humoral response.
Briefly: answers to topical questions
Which enzymes carry out antigen processing for their subsequent presentation in a complex with class I and class II MHC molecules?
Antigen processing is carried out by various enzyme systems depending on the MHC class.
- For class I MHC, the cleavage of intracellular proteins into peptides occurs in the proteasome (immunoproteasome), which possesses chymotrypsin- and trypsin-like activity.
- For class II MHC, the enzymatic cleavage of exogenous proteins is performed by enzymes of antigen-presenting cells inside endosomes and lysosomes. Specific names of enzymes for MHC II are not specified in the sources.
Which transport proteins and chaperones ensure the delivery of peptides into the endoplasmic reticulum and the assembly of the MHC I complex?
The delivery of peptides and the assembly of the MHC I complex are ensured by specialized transport systems and chaperone molecules.
- TAP (Transporter associated with antigen processing) are transport proteins encoded by the TAP1 and TAP2 genes, which transfer peptides from the cytoplasm into the endoplasmic reticulum.
- Calnexin and calreticulin are chaperone molecules that temporarily stabilize the conformation of an empty MHC I molecule until peptide binding occurs, after which they dissociate from the finished complex.
Which molecule prevents the premature binding of the cell's own proteins to the antigen-binding cleft of a class II MHC molecule in the endoplasmic reticulum?
Premature binding of self-peptides to the MHC II molecule is prevented by the invariant chain.
- Invariant chain (Invariant chain, Ii chain) is a special additional polypeptide chain synthesized in the endoplasmic reticulum along with the $\alpha$ and $\beta$ chains of MHC II. It fills the antigen-binding cavity and blocks the active center of the molecule. This is a protective mechanism preventing MHC II from binding to endogenous cell proteins during the transport of the complex to the endosome.
What is the phenomenon of antigen cross-presentation, and which cells are capable of performing it?
The phenomenon of cross-presentation lies in the ability of cells to present exogenous (extracellular) antigens in a complex with class I MHC molecules, which is necessary to trigger a cytotoxic immune response. Normally, exogenous proteins are presented as part of MHC II, but during cross-presentation, they enter the MHC I processing pathway, for example, via retrograde transport from endosomes. In the cited sources, such presentation is described for dendritic cells.
The rule of eights (multiplication): class I MHC molecules always interact with the CD8 receptor ($1 \times 8 = 8$), while class II MHC molecules interact with CD4 ($2 \times 4 = 8$).
Class and exam questions
Where are MHC class I molecules located and where are they absent?
They are present on the membranes of all nucleated cells. Exceptions are erythrocytes, neurons, and villous trophoblast cells.
Which cells are classified as professional antigen-presenting cells?
Professional APCs include macrophages, dendritic cells, and B lymphocytes. Class II MHC molecules are normally present exclusively on them.
What is the difference in the origin of antigens presented by different MHC classes?
MHC I presents endogenous proteins (intracellular ones, e.g., viral or tumor proteins). MHC II molecules present exogenous proteins that have been captured by the cell from the outside via phagocytosis.
What else to study on this topic
- Functions and products of MHC class III genes
- Differentiation pathways of T helper cells and their cytokine profiles
- Structure and function of the proteasome in the processing mechanism
- The role of $\gamma$-interferon in induced molecule expression
- Details of MHC complex transport from the endoplasmic reticulum
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